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A Novel Combination Therapeutic Strategy Aiming to Functional Cure for Chronic Hepatitis B Virus Infection (A)

Hepatitis B virus (HBV) infection is a major public health threat in China. At present, a functional cure, also known as clinical cure or sustained Hepatitis B surface antigen (HBsAg) loss, is recommended as the ideal endpoint of HBV treatment. However, HBsAg loss can be achieved in less than 10% of chronic hepatitis B (CHB) patients treated with current available antiviral drug interferonα (IFNα) or nucleos(t)ide analogues (NAs) monotherapy. With the support of the national major special funding for infectious diseases from "11th Five-Year Plan" to "13th Five-Year Plan", we have implemented a pioneer clinical study of sequential combination of IFNα therapy on NAs to treat NAs-treated CHB patients (ie. New Switch Study). This is the world's first clinical trial aiming to functional cure, which increased the rate of HBsAg loss to 15% in the overall population in our study, and to 30-50% among those with lower baseline HBsAg levels. How to further improve the HBsAg loss rate is an urgent issue for us. The key point of achieving functional cure is to reverse the HBV-specific T cell exhaustion and establish the long-term immune control against HBV infection. Programmed death-1(PD-1)/programmed death-ligand 1 (PD-L1) axis blockade has been demonstrated to reinvigorate exhausted CD8+ T cells, and would be a potential strategy to treat chronic HBV infection. In this study, a large multicenter prospective study will be performed to explore the safety and efficacy of a novel combination strategy involving immune checkpoint inhibitor (anti-PD-1/anti-PD-L1 antibody) and IFNα in CHB patients, observe the HBsAg loss rate in NA-treated CHB patients receiving this combination strategy, evaluate the potential of breaking immune tolerance by this strategy, and further assess its efficacy to further improve the clinical cure rate on the basis of New Switch Study. Based on New Switch Study, this study further attempts to reverse T cell exhaustion in CHB patients, explore a novel platform of combination therapy development for clinical cure, and ultimately increase the HBsAg loss rate to higher than 50% in overall patients. The implementation of the project is expected to reduce the burden of HBV infection in China and contribute to the goal of global elimination of hepatitis B and C by 2030 (WHO 2030).

Studie Overzicht

Toestand

Werving

Conditie

Interventie / Behandeling

Studietype

Ingrijpend

Inschrijving (Geschat)

1200

Fase

  • Fase 2

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Studie Locaties

    • Chongqing Municipality
      • Chongqing, Chongqing Municipality, China, 400010
        • Werving
        • The 2nd affiliated Hospital of Chongqing Medical University
        • Hoofdonderzoeker:
          • HONG REN, Professor
        • Contact:
        • Contact:

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar tot 60 jaar (Volwassen)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

Inclusion Criteria:

  1. Sign the informed consent form before inclusion and be able to complete the study according to the study requirements;
  2. 18-60 years old.
  3. NAs-naive/NAs-experienced CHB patients.

Exclusion Criteria:

  1. A history of allergy, or who are suspected by the researcher to be allergic to the active ingredient of the drug under study or its excipients;
  2. Use of inhibitors, inducers or substrates of CYP3A4 within 28 days before enrollment;
  3. Systematical use of immunosuppressants, immunomodulators (thymosin) and cytotoxic drugs within 6 months before enrollment, or vaccination of live attenuated vaccine within 1 month before enrollment;
  4. Acute infection within 2 weeks before enrollment which requires intravenous antibiotic treatment, or existing infection which requires anti-infection treatment when enrollment;
  5. Clinically significant acute and chronic liver disease not caused by HBV infection (judged by reseachers);
  6. Confirmed or suspected decompensated cirrhosis, including but not limited to: hepatic encephalopathy, hepatorenal syndrome, bleeding from esophageal varices, splenomegaly, ascites, etc, or evidence of progressive liver fibrosis;
  7. Primary liver cancer, or alpha-fetoprotein (AFP) is greater than 50 ug/L or imaging suggests the possibility of malignant liver lesions, or other malignant tumors or a history of other malignant tumors within 5 years before enrollment (except that the malignant tumors have been completely relieved after treatment and patients have not received additional medical or surgical intervention within 3 years before screening);
  8. A history of pathological fracture or osteoporosis;
  9. Gastrointestinal dysfunction or gastrointestinal diseases that might affect the absorption of oral drugs, such as severe gastric ulcer, erosive gastritis, partial gastrectomy, and persistent gastrointestinal symptoms (such as nausea, vomiting, or diarrhea) >2 grades;
  10. Serious diseases of circulatory, respiratory, urinary, blood, metabolic, immune, mental, neurological, renal and other systems;
  11. Major trauma or major surgery within 3 months before enrollment, or planned surgery during the study period;
  12. Blood donation/loss ≥ 400 mL within 3 months before enrollment, or given a blood transfusion within 3 months before enrollment, or blood donation/loss ≥ 200 mL within 1 month before enrollment;
  13. Platelet count<90 × 10^9/L, white blood cell count<3.0 × 10^9/L, neutrophil count<1.3 × 10^9/L, total serum bilirubin>2 × upper limit of normal (ULN), albumin<30 g/L, creatinine clearance ≤ 60 mL/min (calculated by CKD-EPI formula), or international normalized ratio of prothrombin time (INR)>1.5 (unless receiving stable anticoagulant therapy);
  14. Hepatitis C virus (HCV) antibody (+), HIV antigen/antibody (+), or treponema pallidum antibody (+) and rapid plasma regain (RPR) test (+);
  15. A history of continuous alcohol abuse within 3 years before enrollment (average daily alcohol consumption exceeds 20 gram);
  16. A history of drug dependence or drug abuse within 1 year before enrollment;
  17. Those who have participated in clinical trials of other investigational drugs or medical devices and taken investigational drugs or used medical devices within 3 months before enrollment;
  18. Female in suckling period or pregnancy test (+) during screening;
  19. Subjects who are considered by the researcher to have other factors that are not suitable for the study

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: Niet-gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: NAs combined with Sintilimab/Envafolimab

NAs (Once/day, 1 capsule/time, oral)combined with Sintilimab(anti-PD-1 antibody, once/three weeks, dose lower than the dose used in cancer patients, intravenous injection) /Envafolimab(anti-PD-L1 antibody, once/two weeks, dose lower than the dose used in cancer patients, subcutaneous injection), followed by NAs monotherapy

Sintilimab(anti-PD-1 antibody),once/three weeks, dose lower than the dose used in cancer patients, intravenous injection; Envafolimab(anti-PD-L1 antibody),once/two weeks, dose lower than the dose used in cancer patients, subcutaneous injection

Andere namen:
  • Sintilimab(anti-PD-1 antibody)
  • Envafolimab(anti-PD-L1 antibody)

NAs(ETV/TDF/TAF), Once/day, 1 capsule/time, oral

Actieve vergelijker: NAs

NAs(Once/day, 1 capsule/time, oral)

NAs(ETV/TDF/TAF), Once/day, 1 capsule/time, oral

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Serum HBsAg
Tijdsspanne: Baseline

Serum HBsAg level

Baseline
Serum HBsAg
Tijdsspanne: 24 weeks after the treatment

Serum HBsAg level

24 weeks after the treatment
Serum HBsAg
Tijdsspanne: 48 weeks after the treatment

Serum HBsAg level

48 weeks after the treatment
Serum HBsAg
Tijdsspanne: 24 weeks after the end of treatment

Serum HBsAg level

24 weeks after the end of treatment
Serum HBV DNA
Tijdsspanne: Baseline

Serum HBV DNA level

Baseline
Serum HBV DNA
Tijdsspanne: 24 weeks after the treatment

Serum HBV DNA level

24 weeks after the treatment
Serum HBV DNA
Tijdsspanne: 48 weeks after the treatment

Serum HBV DNA level

48 weeks after the treatment
Serum HBV DNA
Tijdsspanne: 24 weeks after the end of treatment

Serum HBV DNA level

24 weeks after the end of treatment
Serum alanine aminotransferase (ALT)
Tijdsspanne: Baseline

Serum ALT level

Baseline
Serum alanine aminotransferase (ALT)
Tijdsspanne: 24 weeks after the treatment

Serum ALT level

24 weeks after the treatment
Serum alanine aminotransferase (ALT)
Tijdsspanne: 48 weeks after the treatment

Serum ALT level

48 weeks after the treatment
Serum alanine aminotransferase (ALT)
Tijdsspanne: 24 weeks after the end of treatment

Serum ALT level

24 weeks after the end of treatment

Andere uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Tijdsspanne: Baseline

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

Baseline
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Tijdsspanne: 24 weeks after the treatment

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

24 weeks after the treatment
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Tijdsspanne: 48 weeks after the treatment

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

48 weeks after the treatment
Other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)
Tijdsspanne: 24 weeks after the end of treatment

Levels of other HBV markers (HBsAb, HBeAg, HBeAb, and HBcAb)

24 weeks after the end of treatment
Immune response of T and B cells
Tijdsspanne: Baseline

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

Baseline
Immune response of T and B cells
Tijdsspanne: 24 weeks after the treatment

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

24 weeks after the treatment
Immune response of T and B cells
Tijdsspanne: 48 weeks after the treatment

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

48 weeks after the treatment
Immune response of T and B cells
Tijdsspanne: 24 weeks after the end of treatment

Frequencies and functions of T and B cells (tested by flowcytometry/FluoroSpot/ELISPOT)

24 weeks after the end of treatment
Virus and host genome
Tijdsspanne: Baseline

Detect virus and host genome using peripheral blood and liver tissue by sequencing

Baseline
Virus and host genome
Tijdsspanne: 24 weeks after the treatment

Detect virus and host genome using peripheral blood and liver tissue by sequencing

24 weeks after the treatment
Virus and host genome
Tijdsspanne: 48 weeks after the treatment

Detect virus and host genome using peripheral blood and liver tissue by sequencing

48 weeks after the treatment
Virus and host genome
Tijdsspanne: 24 weeks after the end of treatment

Detect virus and host genome using peripheral blood and liver tissue by sequencing

24 weeks after the end of treatment

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Medewerkers

Onderzoekers

  • Studie directeur: Hong Ren, MM, The Second Affiliated Hospital of Chongqing Medical University

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

10 oktober 2023

Primaire voltooiing (Geschat)

31 december 2026

Studie voltooiing (Geschat)

31 december 2026

Studieregistratiedata

Eerst ingediend

21 september 2026

Eerst ingediend dat voldeed aan de QC-criteria

29 september 2026

Eerst geplaatst (Werkelijk)

1 oktober 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

1 oktober 2026

Laatste update ingediend die voldeed aan QC-criteria

29 september 2026

Laatst geverifieerd

1 september 2026

Meer informatie

Termen gerelateerd aan deze studie

Andere studie-ID-nummers

  • 2025-0215

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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